Methods of treating alpha adrenergic mediated conditions

ABSTRACT

Described herein are compounds for and methods of treating conditions or diseases in a subject by administering to the subject a pharmaceutical composition containing an effective amount of an α-adrenergic modulator. The compounds and methods are also useful for alleviating types of pain, both acute and chronic.

CROSS-REFERENCE TO RELATED APPLICATION

This application is based, and claims priority under 35 U.S.C. §120 toU.S. Provisional Patent Application No. 61/059,837 filed on Jun. 9,2008, and which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods of using compounds as disclosedherein to treat pain.

BACKGROUND OF THE INVENTION

Clinical pain encompasses nociceptive and neuropathic pain. Each type ofpain is characterized by hypersensitivity at the site of damage and inadjacent normal tissue. While nociceptive pain usually is limited induration and responds well to available opioid therapy, neuropathic paincan persist long after the initiating event has healed, as is evident,for example, in the “ghost pain” that often follows amputation. Chronicpain syndromes such as chronic neuropathic pain are triggered by any ofa variety of insults, including surgery, compression injury or trauma,infectious agent, toxic drug, inflammatory disorder, or a metabolicdisease such as diabetes or ischemia.

Unfortunately, chronic pain such as chronic neuropathic pain generallyis resistant to available drug therapy. Furthermore, current therapieshave serious side-effects such as cognitive changes, sedation, nauseaand, in the case of narcotic drugs, addiction. Many patients sufferingfrom neuropathic and other chronic pain are elderly or have medicalconditions that limit their tolerance to the side-effects associatedwith available analgesic therapy. The inadequacy of current therapy inrelieving neuropathic pain without producing intolerable side-effectsoften is manifest in the depression and suicidal tendency of chronicpain sufferers.

As alternatives to current analgesics, α₂ adrenergic agonists, which aredevoid of respiratory depressant effects and addictive potential arebeing developed. Such drugs are useful analgesic agents whenadministered spinally. However, undesirable pharmacological propertiesof α-adrenergic agonists, specifically sedation and hypotension, limitthe utility of these drugs when administered orally or by otherperipheral routes. Thus, there is a need for effective analgesic agentsthat can be administered by oral or other peripheral routes and thatlack undesirable side-effects such as sedation and hypotension. Thepresent invention satisfies this need and provides related advantages aswell.

Also provided herein are new therapies for chronic pain sufferers, who,until now, have faced a lifetime of daily medication to control theirpain. Unfortunately, available treatments for chronic neuropathic pain,such as tricyclic antidepressants, anti-seizure drugs and localanesthetic injections, only alleviate symptoms temporarily and tovarying degrees. No available treatment reverses the sensitized painstate or cures pain such as neuropathic pain. Effective drugs that canbe administered, for example, once or several times a month and thatmaintain analgesic activity for several weeks or months, are presentlynot available. Thus, there is a need for novel methods of providinglong-term relief from chronic pain. The present invention satisfies thisneed and also provides related advantages.

SUMMARY OF THE INVENTION

Described herein are compounds for and methods of treating conditions ordiseases in a subject by administering to the subject a pharmaceuticalcomposition containing an effective amount of an α-adrenergic modulator.The compounds and methods are also useful for alleviating types of pain,both acute and chronic.

Described herein is a method of treating a condition or diseasealleviated by activation of α-adrenergic receptors in a mammalcomprising: administering a compound having a structure

wherein R¹ and R² are each independently selected from hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy, OH, halogen, NR′₂, CN, CO₂R′, C(O)NR′R″, alcohol,C₁₋₄ halogenated alkyl, C₁₋₄ halogenated alkoxy, and substituted orunsubstituted aryl or heteroaryl; R′ is selected from hydrogen, C₁₋₄alkyl and C₁₋₄ halogenated alkyl, substituted or unsubstituted aryl orheteroaryl; R″ is selected from hydrogen and C₁₋₄ alkyl, substituted orunsubstituted aryl or heteroaryl; and wherein the compound activates atleast one of the α adrenergic receptors.

Also described herein is a composition for treating a condition ordisease alleviated by activation of α-adrenergic receptors in a mammalcomprising: a compound having a structure

wherein R¹ and R² are each independently selected from hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy, OH, halogen, NR′₂, CN, CO₂R′, C(O)NR′R″, alcohol,C₁₋₄ halogenated alkyl, C₁₋₄ halogenated alkoxy, and substituted orunsubstituted aryl or heteroaryl; R′ is selected from hydrogen, C₁₋₄alkyl and C₁₋₄ halogenated alkyl, substituted or unsubstituted aryl orheteroaryl; R″ is selected from hydrogen and C₁₋₄ alkyl, substituted orunsubstituted aryl or heteroaryl; and wherein the compound activates atleast one of the α-adrenergic receptors.

In one embodiment, the condition or disease is selected from the groupconsisting of hypertension, congestive heart failure, asthma,depression, glaucoma, elevated intraocular pressure, ischemicneuropathies, optic neuropathy, pain, visceral pain, corneal pain,headache pain, migraine, cancer pain, back pain, irritable bowelsyndrome pain, muscle pain, pain associated with diabetic neuropathy,the treatment of diabetic retinopathy, other retinal degenerativeconditions, stroke, cognitive deficits, neuropsychiatric conditions,drug dependence, drug addiction, withdrawal symptoms, obsessivecompulsive disorder, obesity, insulin resistance, stress relatedconditions, diarrhea, diuresis, nasal congestions, spasticity, attentiondeficit disorder, psychoses, anxiety, autoimmune disease, Crohn'sdisease, gastritis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, and other neurodegenerative diseases. Inone embodiment, the condition or disease is pain.

In one embodiment, R¹ and R² are each independently a halogen orhalogenated alkyl. In another embodiment, the compound isN-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine. Inanother embodiment, the compound isN-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.In another embodiment, the compound isN-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2,3-dimethylbenzyl)-4,5-dihydro-1H-imidazol-2-amine. In anotherembodiment, the compound isN-(2-fluorobenzyl)-4,5-dihydro-1H-imidazol-2-amine.

In one embodiment, the compound is selected from the group consisting ofN-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2,3-dimethylbenzyl)-4,5-dihydro-1H-imidazol-2-amine,N-(2-fluorobenzyl)-4,5-dihydro-1H-imidazol-2-amine, and combinationsthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the peripheral analgesic effects of a single oral dose ofN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine in Chung modelrats at 30 μg/kg, 100 μg/kg or 300 μg/kg.

FIG. 2 depicts sedative effects (total activity counts) 30 minutes postintraperitoneal injection of 1 mg/kg and 10 mg/kg doses ofN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine.

DEFINITION OF TERMS

Prodrug: A “prodrug” is a compound which is converted to atherapeutically active compound after administration. While notintending to limit the scope, conversion may occur by hydrolysis of anester group or some other biologically labile group. Prodrug preparationis well known in the art. For example, “Prodrugs and Drug DeliverySystems,” which is a chapter in Richard B. Silverman, Organic Chemistryof Drug Design and Drug Action, 2d Ed., Elsevier Academic Press:Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

Halogen: As used herein, “halogen” is used to refer to a substituentfound in column VIIA of the periodic table of elements, includingfluorine, chlorine, bromine, and iodine.

Tautomer: As used herein, “tautomer” refers to the migration of protonsbetween adjacent single and double bonds. The tautomerization process isreversible. Compounds described herein can undergo the followingtautomerization:

DETAILED DESCRIPTION OF THE INVENTION

Described herein are N-(2 and/or 3-substitutedbenzyl)-4,5-dihydro-1H-imidazol-2-amine compounds as subtype selectiveα_(2A) and/or α_(2C) adrenergic modulators having the general structure

wherein R¹ and R² are each independently selected from hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy, OH, halogen, NR′₂, CN, CO₂R′, C(O)NR′R″, alcohol,C₁₋₄ halogenated alkyl, C₁₋₄ halogenated alkoxy, and substituted orunsubstituted aryl or heteroaryl; R′ is selected from hydrogen, C₁₋₄alkyl and C₁₋₄ halogenated alkyl, substituted or unsubstituted aryl orheteroaryl; and R″ is selected from hydrogen and C₁₋₄ alkyl, substitutedor unsubstituted aryl or heteroaryl.

In one embodiment, wherein R¹ and R² are each independently selectedfrom hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, OH, halogen, NR′₂, CN, CO₂R′,C(O)NR′R″, alcohol, C₁₋₁₀ halogenated alkyl, C₁₋₁₀ halogenated alkoxy,and substituted or unsubstituted aryl or heteroaryl; R′ is selected fromhydrogen, C₁₋₁₀ alkyl and C₁₋₁₀ halogenated alkyl, substituted orunsubstituted aryl or heteroaryl; and R″ is selected from hydrogen andC₁₋₁₀ alkyl, substituted or unsubstituted aryl or heteroaryl.

R¹ and R² can each independently be a C₁₋₁₀ alkyl, which includes C₃₋₁₀cycloalkyls and C₃₋₁₀ branched alkyls. R¹ and R² can each alsoindependently be a substituted or unsubstituted aryl or heteroaryl whichcan include aromatic, heteroaromatic, or multi-heteroaromatic groups.The substituted or unsubstituted aryl or heteroaryl can be selected fromphenyl, pyridinyl, thienyl, furyl, naphthyl, quinolinyl, indanyl orbenzofuryl. Exemplary substituted or unsubstituted aryls or heteroarylsinclude, but are not limited to, benzenes, pyrideines, thiophenes,furans, naphthalenes, quinolines, indans and benzofurans. The arylgroups may be substituted with any common organic fictional group. Sucharyl groups may be bonded to Formula 1 at any available position on thearyl group.

An exemplary aryl group is a benzene (Formula 2):

wherein at least one of R⁴⁻⁹ must be Formula 1 and wherein the remainingR⁴⁻⁹ may be each independently substituted with a common organicfunctional group including, but not limited to, hydrogen, a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, thiol, or carboxy group subsitiuted with a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, or thiol group.

Another aryl group may be a pyridine as in Formula 3:

wherein at least one of R⁴⁻⁸ must be Formula 1 and wherein the remainingR⁴⁻⁸ may be each independently substituted with a common organicfunctional group including, but not limited to, hydrogen, a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, thiol, or carboxy group subsitiuted with a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, or thiol group.

Another aryl group may be a thiophene as in Formula 4:

wherein at least one of R⁴⁻⁷ must be Formula 1 and wherein the remainingR⁴⁻⁷ may be each independently substituted with a common organicfunctional group including, but not limited to, hydrogen, a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, thiol, or carboxy group subsitiuted with a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, or thiol group.

Another aryl group may be a furan as in Formula 5:

wherein at least one of R⁴⁻⁷ must be Formula 1 and wherein the remainingR⁴⁻⁷ may be each independently substituted with a common organicfunctional group including, but not limited to, hydrogen, a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, thiol, or carboxy group subsitiuted with a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, or thiol group.

Another aryl group may be a naphthalene as in Formula 6:

wherein at least one of R⁴⁻¹¹ must be Formula 1 and wherein theremaining R⁴⁻¹¹ may be each independently substituted with a commonorganic functional group including, but not limited to, hydrogen, aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, thiol, or carboxy group subsitiuted with aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, or thiol group.

Another aryl group may be a quinoline as in Formula 7:

wherein at least one of R⁴⁻¹⁰ must be Formula 1 and wherein theremaining R⁴⁻¹⁰ may be each independently substituted with a commonorganic functional group including, but not limited to, hydrogen, aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, thiol, or carboxy group subsitiuted with aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, or thiol group.

Another aryl group may be an indan as in Formula 8:

wherein at least one of R⁴⁻¹³ must be Formula 1 and wherein theremaining R⁴⁻¹³ may be each independently substituted with a commonorganic functional group including, but not limited to, hydrogen, aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, thiol, or carboxy group subsitiuted with aC₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl,alkoxy, amino, cyano, nitro, or thiol group.

Another aryl group may be a benzofuran as in Formula 9:

wherein at least one of R⁴⁻⁹ must be Formula 1 and wherein the remainingR⁴⁻⁹ may be each independently substituted with a common organicfunctional group including, but not limited to, hydrogen, a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, thiol, or carboxy group subsitiuted with a C₁₋₁₀ alkyl,C₁₋₁₀ alkenyl, C₁₋₁₀ alkynl, aryl, halogen, hydroxyl, alkoxy, amino,cyano, nitro, or thiol group.

α₂ adrenergic receptors have been characterized by molecular andpharmaceutical methods; the methods including α_(1A), α_(1B), α_(1D),α_(2A), α_(2B) and α^(2C) subtypes. Activation of these α-receptors canevoke physiological responses. Adrenergic modulators described hereinactivate one or both of the α_(2B) and/or α_(2C) receptors and haveuseful therapeutic actions.

The following structures are contemplated according to the presentdescription.

The compounds described herein may be useful for the treatment of a widerange of conditions and diseases that are alleviated by α_(2B) and/orα_(2C) activation including, but not limited to, hypertension,congestive heart failure, asthma, depression, glaucoma, elevatedintraocular pressure, ischemic neuropathies, optic neuropathy, pain,visceral pain, corneal pain, headache pain, migraine, cancer pain, backpain, irritable bowel syndrome pain, muscle pain, pain associated withdiabetic neuropathy, the treatment of diabetic retinopathy, otherretinal degenerative conditions, stroke, cognitive deficits,neuropsychiatric conditions, drug dependence, drug addiction, withdrawalsymptoms, obsessive compulsive disorder, obesity, insulin resistance,stress related conditions, diarrhea, diuresis, nasal congestions,spasticity, attention deficit disorder, psychoses, anxiety, autoimmunedisease, Crohn's disease, gastritis, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, and other neurodegenerativediseases.

Applicants have discovered that these compounds activate or modulateα_(2B) and α_(2C) receptors. Additionally, these compounds act as ahighly effective analgesic, particularly in chronic pain models, withminimal undesirable side effects, such as sedation and cardiovasculardepression, commonly seen with agonists of α_(2B) and α_(2C) receptors.

Such compounds may be administered at pharmaceutically effectivedosages. Such dosages are normally the minimum dose necessary to achievethe desired therapeutic effect; in the treatment of chromic pain, thisamount would be roughly that necessary to reduce the discomfort causedby the pain to tolerable levels. Generally, such doses will be in therange 1-1000 mg/day; more preferably in the range 10 to 500 mg/day.However, the actual amount of the compound to be administered in anygiven case will be determined by a physician taking into account therelevant circumstances, such as the severity of the pain, the age andweight of the patient, the patient's general physical condition, thecause of the pain, and the route of administration.

The compounds may be useful in the treatment of pain in a mammal,particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without limitation, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Another embodiment is drawn to therapeutic compositions comprising thecompounds of Formula 1, pharmaceutically acceptable derivatives, salts,prodrugs and/or combinations of these compounds and a pharmaceuticallyacceptable excipient. Such an excipient may be a carrier or a diluent;this is usually mixed with the active compound, or permitted to diluteor enclose the active compound. If a diluent, the carrier may be solid,semi-solid, or liquid material that acts as an excipient or vehicle forthe active compound. The formulations may also include wetting agents,emulsifying agents, preserving agents, sweetening agents, and/orflavoring agents. If used as in an ophthalmic or infusion format, theformulation will usually contain one or more salt to influence theosmotic pressure of the formulation.

Another embodiment is directed to methods for the treatment of pain,particularly chronic pain, through the administration of a compound ofFormula 1, and pharmaceutically acceptable salts, and derivativesthereof to a mammal in need thereof. As indicated above, the compoundwill usually be formulated in a form consistent with the desired mode ofdelivery.

Some embodiments provide methods that rely on administration of one ormore pharmaceutical compositions to a subject. As used herein, the term“subject” means any animal capable of experiencing pain, for example, ahuman or other mammal such as a primate, horse, cow, dog or cat.

The methods described herein are used to treat both acute and chronicpain, and, as non-limiting examples, pain which is neuropathic, visceralor inflammatory in origin. In particular embodiments, the methods of theinvention are used to treat neuropathic pain; visceral pain;post-operative pain; pain resulting from cancer or cancer treatment; andinflammatory pain.

Both acute and chronic pain can be treated by the methods describedherein, and the term “pain” encompasses both acute and chronic pain. Asused herein, the term “acute pain” means immediate, generally highthreshold, pain brought about by injury such as a cut, crush, burn, orby chemical stimulation such as that experienced upon exposure tocapsaicin, the active ingredient in chili peppers. The term “chronicpain,” as used herein, means pain other than acute pain and includes,without limitation, neuropathic pain, visceral pain, inflammatory pain,headache pain, muscle pain and referred pain. It is understood thatchronic pain is of relatively long duration, for example, several yearsand can be continuous or intermittent.

Unless otherwise indicated, reference to a compound should be construedbroadly to include compounds, pharmaceutically acceptable salts,prodrugs, tautomers, alternate solid forms, non-covalent complexes, andcombinations thereof, of a chemical entity of a depicted structure orchemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acid/carboxylate), one or more protonated basic groups (e.g.amine/ammonium), or both (e.g. zwitterions).

A prodrug is a compound which is converted to a therapeutically activecompound after administration. For example, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion. Not intended to be limited by the above describedcompounds, various tautomers of the above compounds may be possible. Forexample, not intended as a limitation, tautomers are possible betweenthe 4,5-dihydrooxazole and the adjacent nitrogen as shown below.

Other tautomers are possible when the compound includes, for example butnot limited to, enol, keto, lactamin, amide, imidic acid, amine, andimine groups. Tautomers will generally reach an equilibrium statewherein the double bond is resonantly shared between the two bondlengths.

Unless stereochemistry is explicitly and unambiguously depicted, astructure is intended to include every possible stereoisomer, both pureor in any possible mixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

The following examples provide synthesis methods for forming compoundsdescribed herein. One skilled in the art will appreciate that theseexamples can enable a skilled artisan to synthesize the compoundsdescribed herein.

EXAMPLE 1 Generic Reaction 1

In scheme A above, Formula 11 was either commercially available orsynthesized by different reductive amination methods from Formula 10.One of those methods was published by David J. H. et al (J. Org. Chem.48: 289-294 (1983)). The key step was the coupling for Formula 11 withimidazoline which had an appropriate leaving group on the secondposition to give Formula 12. The leaving group may be methylthiol(R═(O)COMe) or sulfuric acid (R═H). There are also other known couplingprocedures known by those skilled in the art or by modifications ofknown procedures known by those skilled in the art.

In Scheme B, another method is depicted to synthesize Formula 11 fromsubstituted benzoic acid, substituted ester or substituted benzylalcohol, all of which are commercially available. Formula 13 wasconverted to an ester which can be reduced to Formula 14 with lithiumaluminum hydride (LAH) or borane as reagents. Conversion of the alcohol,Formula 14, to the azide, Formula 15, may be accomplished by methodssuch as Mitsunobu reaction with diphenylphosphoryl azide in one step, orconverting alcohol to a good leaving group which can be replaced withazide anion. Denitrogenation of azide to amine was carried out with aphosphine such as triphenyl phosphine. Subsequent basic hydrolysisliberated the intermediate to amine.

The compounds described herein may also be synthesized by other methodsknown by those skilled in the art.

EXAMPLE 2 Synthesis ofN-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine

To a 7.08 mmol solution of 2-chloro-3-fluorobenzaldehyde 1 (1.00 g,commercially available from 3B Medical Systems, Inc.) in 8.0 mL oftetrahydrofuran (THF) was added 8.50 mL of 1.0M lithiumbis(trimethylsilyl)-amide via syringe at 0° C. The resulting solutionwas stirred at 0° C. for 3 hours. 8.50 mL of 1.0M LAH was added viasyringe. Three hours later, the reaction mixture was carefully pouredonto crushed ice. Ammonium chloride (aq) and Rochelle's salt (aq) wereadded to this mixture. The aqueous layer was extracted three times with200 mL of chloroform/isopropanol (3:1). The pooled organic layer wasdried over magnesium sulfate. The mixture was filtered, and the solventswere removed under vacuum to give (2-cholor-3-fluorophenyl)methanamine2. The weight of the product was 0.92 g.

A mixture of 0.92 g of (2-cholor-3-fluorophenyl)methanamine 2 and 0.790g of 4,5-dihydro-1H-imidazole-2-sulfonic acid (commercially availablefrom Astatech) in 10.0 mL of ethanol was heated in a sealed tube to 90°C. for 16 hours. Then, the reaction mixture was cooled to roomtemperature. Next, the ethanol was removed under vacuum. The remainingresidue was basified with aqueous sodium bicarbonate solution and the pHwas adjusted to about 10 with 2M sodium hydroxide. The aqueous layer wasextracted three times with 100 mL of chloroform/isopropanol (3:1). Thepooled organic layer was dried over magnesium sulfate and the mixturewas then filtered. Amino-modified silica gel was added to the filtrateand the solvents were removed under vacuum. Purification bychromatorography on amino-modified silica gel (3.5% methanol indichloromethane afforded 0.575 g ofN-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine 3 as ayellow solid.

¹H NMR (300 MHz, CD₃OD): δ 7.32-7.21 (m, 2H), 7.15-7.09 (m, 1H), 4.42(s, 2H), 3.48 (s, 4H).

The following compounds can also be prepared according to Example 2.

N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR(300 MHz, CD₃OD): δ=7.43-7.32 (m, 2H), 7.24-7.16 (m, 2H), 6.90 (t,J=73.8 Hz, 1H), 4.43 (s, 2H), 3.62 (s, 4H).

N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300MHz, CD₃OD): δ=7.11-7.04 (m, 3H), 4.33 (s, 2H), 3.56 (s, 4H).

N-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300MHz, CD₃OD): δ=7.76-7.65 (m, 2H), 7.58-7.50 (m, 2H), 4.61 (s, 2H), 3,74(s, 4H).

N-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300MHz, CD₃OD): δ=7.51-7.48 (m, 1H), 7.39-7.28 (m, 3H), 4.45 (s, 2H), 3.60(s, 4H).

N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300 MHz,CD₃OD): δ=7.40 (t, J=7.5 Hz, 1H), 7.28 (q, J=7.2 Hz, 1H), 7.11-7.03 (m,2H), 4.41 (s, 2H), 3.56 (s, 4H).

N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine:¹H NMR (300 MHz, CD₃OD): δ=7.66 (t, J=7.5 Hz, 1H), 7.57 (q, J=7.5 Hz,1H), 7.30 (t, J=7.5 Hz, 1H), 4.42 (s, 2H), 3.50 (s, 4H).

N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300MHz, CD₃OD): δ=7.05-6.87 (m, 3H), 4.34 (s, 2H), 3.83 (s, 6H), 3.55 (s,4H).

EXAMPLE 3 Synthesis ofN-(3-bromo-2-methoxy-benzvl)-4,5-dihydro-1H-imidazol-2-amine

5.0 mL of sulfuric acid (H₂SO₄) was slowly added to a solution of 5.0 gof 3-bromo-2-methoxy-benzoic acid 4 in 100 mL of methanol (MeOH). Theresulting solution was heated to reflux overnight. The solution wascooled to room temperature and quenched with sodium bicarbonate to pH 7.The aqueous layer was extracted several times with ethyl acetate. Thecombined organic extracts were washed with brine and dried over sodiumsulphate. The resulting mixture was filtered. The solvents wereevaporated under reduced pressure to afford 5.3 g of3-bromo-2-methoxy-benzoic acid methyl ester 5.

2.4 g of lithium borohydride (LiBH₄) was added to a solution of 5.3 g of3-bromo-2-methoxy-benzoic acid methyl ester 5 in 200 mL of ether (Et₂O)at 0° C. After stirring for 5 minutes, 5 mL of methanol was added. Thereaction mixture was warmed to room temperature and kept there for 2.5hours. Thereafter, 2.4 g more of lithium borohydride was added. Thereaction mixture was quenched with aluminum chloride. After standardaqueous work up, and silica gel column purification (hexane/ethylacetate 2:1), 4.0 g of 3-bromo-2-methoxy-phenyl-methanol 6 was obtained.

6.00 g of diphenyl phosphorazidate and 4.1 g of1,8-diazabicyclo[5.4.0]undec-7-ene were added to 4.0 g of3-bromo-2-methoxy-phenyl-methanol 6 in 100 mL of toluene at 0° C. Themixture was stirred at room temperature overnight. The reaction mixturewas quenched with aqueous ammonium chloride. The aqueous layer wasextracted with ethyl acetate/THF. The pooled organic extracts werewashed with brine and dried over magnesium sulfate. The mixture wasfiltered. The solvents were removed under vacuum. The residue waspurified by chromatography on silica gel to give1-azidomethyl-3-bromo-2-methoxy-benzene 7.

1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phophine(Ph₃P) were added to a solution of1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL ofwater. The mixture was stirred overnight at room temperature. Themixture was quenched with aqueous concentrated hydrochloride. Afterstandard acid/base aqueous work up, 3.9 g of crude3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps).

10 mL of acetic acid (HOAc) was added to a solution of 3.9 g of3-bromo-2-methoxy-benzylamine 8 and 3.1 g of methyl2-(methylthio)-4,5-hihydro-1H-imidazole-1-carboxylate in 100 mL ofmethanol. The resulting solution was heated to a gentle reflux andrefluxed overnight. The solution was cooled to room temperature,quenched with sodium hydroxide and extracted with ethyl acetate. Thecombined organic extracts were washed with brine and dried overmagnesium sulfate. The mixture was then filtered. The solvents wereremoved under vacuum. The remaining residue was purified bychromatography on silica gel (10% saturated ammonia methanol indichloromethane) to give(3-bromo-2-methoxy-benzyl-4,5-dihydro-1H-imidazol-2-yl)-amine 9.

¹H NMR (300 MHz, CD₃OD): δ=7.51 (d, J=3 Hz, 1H), 7.25-7.29 (m, 1H), 6.80(d, J=9 Hz, 1H), 4.46 (s, 2H), 3.84 (s, 4H), 3.63 (s, 3H).

The following compounds can also be prepared according to Example 3.

N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300 MHz,CD₃OD): δ=7.51-7.53 (m, 1H), 7.28-7.29 (m, 1H), 7.14-7.21 (m, 2H), 4.59(s, 2H), 3.58 (s, 4H).

N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR (300 MHz,CD₃OD): δ=7.08-7.12 (m, 4H), 4.45(d, J=6Hz, 2H), 3.54 (s, 4H), 2.28 (s,3H).

N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine: ¹H NMR(300 MHz, CD₃OD): δ=7.40-7.31 (m, 2H), 7.16-67.10 (m, 1H), 4.42 (s, 2H),3.56 (s, 4H).

EXAMPLE 4 Synthesis ofN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine

A mixture of 5.32 g of (2,3-dichlorophenyl)methanamine 10 and 4.56 g of4,5-hihydro-1H-imidazole-2-sulfonic acid are mixed in 40.0 mL ethanol(EtOH) and heated in a sealed tube at 90° C. for 16 hours. Then, thereaction mixture was cooled to room temperature. Next, the ethanol wasremoved under vacuum. The remaining residue was basified with aqueoussodium bicarbonate solution and the pH was adjusted to about 10 with 2Msodium hydroxide. The aqueous layer was extracted three times with 400mL of chloroform/isopropanol (3:1). The pooled organic layer was driedover magnesium sulfate and the mixture was then filtered. The filtratewas added to amino-modified silica gel (4-5% methanol indichloromethane) and afforded 3.99 g of Compound 11 as a yellow solid.

¹H NMR (300 MHz, CD₃OD): δ 7.43 (dd, J=7.8, 1.8 Hz, 1H, 7.37-7.33 m,1H), 7.26 (t, J=7.8 Hz, 1H), 4.43 (s, 2H), 3.51 (s, 4H)

EXAMPLE 5 Biological Intrinsic Activity Data

Certain compounds described herein were tested for α-adrenergic activityusing the Receptor Selection and Amplification Technology (RSAT) assay(Messier et al., 1995, Pharmacol. Toxicol. 76, pp. 308-311). Cellsexpressing each of the c₂ adrenergic receptors alone were incubated withthe various compounds and a receptor-mediated growth response wasmeasured. The compound's activity is expressed as its relative efficacycompared to standard full agonist (see Table 1 below). The compoundsdescribed herein activate α_(2B) and/or α_(2C) receptors.

Compound α_(1A) α_(2B) α_(2C)

587 (1.01) 33 (1.11) 484 (0.60)

345 (1.12) 50 (0.81) 471 (0.86)

430 (0.79) 56 (0.92) 1594 (0.63)

nd 499 (0.73) nd

282 (1.10) 14.0 (0.94) 46.8 (0.48) nd = not determined

EXAMPLE 6 Biological Intrinsic Activity Data

Various concentrations ofN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine were administeredorally to Chung model rats. A model in accordance with Kim and Chung1992, Pain 150, pp 355-363 (Chung model), for chronic pain (inparticular peripheral neuropathy) involves the surgical ligation of theL5 (and optionally the L6) spinal nerves on one side in experimentalanimals. Rats recovering from the surgery gain weight and display alevel of general activity similar to that of normal rats. However, theserats develop abnormalities of the foot, wherein the hindpaw ismoderately everted and the toes are held together. More importantly, thehindpaw on the side affected by the surgery appears to become sensitiveto pain from low-threshold mechanical stimuli, such as that producing afaint sensation of touch in a human, within about 1 week followingsurgery. This sensitivity to normally non-painful touch is called“tactile allodynia” and lasts for at least two months. The responseincludes lifting the affected hindpaw to escape from the stimulus,licking the paw and holding it in the air for many seconds. None ofthese responses is normally seen in the control group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra XIII down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, typically six rats per test group are administeredthe test drugs by intraperitoneal (i.p.) injection or oral gavage. Fori.p. injection, the compounds are formulated in d H₂O and given in avolume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage needlethat is slowly inserted through the esophagus into the stomach.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by reference.The post-drug threshold is compared to the pre-drug threshold and thepercent reversal of tactile sensitivity is calculated based on a normalthreshold of 15.1 grams.

Table 2 below shows the peak allodynia reversal at 30 μg/kg, 100 μg/kgor 300 μg/kg doses.

TABLE 2 Peak Allodynia Reversal Dose (Oral, 30 min.) 300 μg/kg 84% +/−7.5% 100 μg/kg  68% +/− 12.7%  30 μg/kg 28% +/− 9.5%

As shown in Table 2, 30 μg/kg oral dosage resulted in 28% allodyniareversal. The analgesic effect was seen quickly, in about 30 minutes.FIG. 1 shows a peak percent allodynia reversal at 30 minutes followed bya steady decrease to baseline at about 120 minutes.

EXAMPLE 7 In Vivo Activity Data

Data was acquired from wild type rats administeredN-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine intraperitoneally(IP). Rats were split into groups of six and administered 1 mg/kg or 10mg/kg doses of N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine toassess the sedative effects of the administration of the agent. As canbe seen in both FIG. 2 and Table 3, 10 mg/kg had a significant sedativeeffect on the dosed rats.

TABLE 3 Dose Sedative Effect (IP)  1 mg/kg No significant effect 10mg/kg 23% sedating

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A method of treating a condition or disease alleviated by activation of α-adrenergic receptors in a mammal comprising: administering a compound having a structure

wherein R¹ and R² are each independently selected from hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, halogen, NR′₂, CN, CO₂R′, C(O)NR′R″, alcohol, C₁₋₄ halogenated alkyl, C₁₋₄ halogenated alkoxy, and substituted or unsubstituted aryl or heteroaryl; R′ is selected from hydrogen, C₁₋₄ alkyl and C₁₋₄ halogenated alkyl, substituted or unsubstituted aryl or heteroaryl; R″ is selected from hydrogen and C₁₋₄ alkyl, substituted or unsubstituted aryl or heteroaryl; and wherein said compound activates at least one of said α-adrenergic receptors; wherein said condition or disease is selected from the group consisting of pain, visceral pain, corneal pain, headache pain, cancer pain, back pain, irritable bowel syndrome pain, muscle pain, or pain associated with diabetic neuropathy.
 2. The method according to claim 1 wherein R1 and R2 are each independently a halogen or halogenated alkyl.
 3. The method according to claim 1 wherein said compound is N-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 4. The method according to claim 1 wherein said compound is N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 5. The method according to claim 1 wherein said compound is N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 6. The method according to claim 1 wherein said compound is N -(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 7. The method according to claim 1 wherein said compound is N -(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 8. The method according to claim 1 wherein said compound is N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 9. The method according to claim 1 wherein said compound is N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 10. The method according to claim 1 wherein said compound is N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 11. The method according to claim 1 wherein said compound is N-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 12. The method according to claim 1 wherein said compound is N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 13. The method according to claim 1 wherein said compound is N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 14. The method according to claim 1 wherein said compound is N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
 15. The method according to claim 1 wherein said compound is N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine.
 16. The method according to claim 1 wherein said compound is N-(2,3-dimethylbenzyl)-4,5-dihydro-1H-imidazol-2-amine.
 17. The method according to claim 1 wherein said compound is N-(2-fluorobenzyl)-4,5-dihydro-1H-imidazol-2-amine. 